CAPIVADX 160 (Capivasertib)

About Capivasertib

Capivasertib is an orally bioavailable, small-molecule inhibitor of all three AKT isoforms. Capivasertib used in combination with fulvestrant , is indicated for adults with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations,  following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within twelve months of completing adjuvant therapy.

Breast Cancer

Indicated in combination with fulvestrant for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with ≥1 PIK3CA/AKT1/PTEN-alterations, following progression on at least 1 endocrine-based regimen in the metastatic setting; or recurrence during, or within 12 months after completing, adjuvant therapy

Capivasertib weekly dose schedule

• 400 mg PO BID (~12 hr apart) x 4 consecutive days followed by 3 days off
• Repeat weekly schedule until disease progression or unacceptable toxicity

Fulvestrant regimen during clinical trial

• 28-day cycles
• Cycle 1: 500 mg IM on Days 1 and 15
• Subsequent cycles: 500 mg IM on Day 1
• Premenopausal and perimenopausal women: Administer a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards
• Men: Consider administering a LHRH agonist according to current clinical practice standards

Dosage Modifications

Dose reductions for adverse reactions

• First dose reduction: 320 mg BID x 4 days followed by 3 days off
• Second dose reduction: 200 mg BID x 4 days followed by 3 days off

Hyperglycemia

• Note that recommendations are based on fasting glucose (FG) rather than random glucose

• FG >ULN-160 mg/dL (8.9 mmol/L) or hemoglobin A1C (HbA1C) >7%

  • Consider initiation or intensification of oral antidiabetic treatment

• FG 161-250 mg/dL (9-13.9 mmol/L)

  • Withhold until FG decrease to ≤160 mg/dL (≤8.9 mmol/L)
  • If recovery occurs in ≤28 days, resume at same dose
  • If recovery occurs in >28 days, resume at 1 lower dose

• FG 251-500 mg/dL (14-27.8 mmol/L)

  • Withhold until FG decrease to ≤160 mg/dL (≤8.9 mmol/L)
  • If recovery occurs in ≤28 days, resume at 1 lower dose
  • If recovery occurs in >28 days, permanently discontinue

• FG >500 mg/dL (>27.8 mmol/L) or life-threatening sequelae of hyperglycemia at any FG level

  • Life-threatening sequelae of hyperglycemia or if FG persists at ≥500 mg/dL after 24 hr: Permanently discontinue
  • If FG ≤500 mg/dL (or ≤27.8 mmol/L) within 24 hr, follow above guidance for relevant grade

Diarrhea

• Grade 2

  • Withhold until recovery to Grade ≤1
  • If recovery occurs in ≤28 days: Resume at same dose or 1 lower dose as clinically indicated
  • If recovery occurs in >28 days: Resume at 1 lower dose
  • For recurrence: Reduce by 1 lower dose

• Grade 3

  • Withhold until recovery to Grade ≤1
  • If recovery occurs in ≤28 days: Resume at same dose or 1 lower dose as clinically indicated
  • If recovery occurs in >28 days: Permanently discontinue

• Grade 4

  • Permanently discontinue

Cutaneous reactions

• Grade 2

  • Withhold until recovery to Grade ≤1 then resume at same dose
  • Persistent or recurrent: Reduce by 1 lower dose

• Grade 3

  • Withhold until recovery to Grade ≤1
  • If recovery occurs in ≤28 days: Resume at same dose
  • If recovery occurs in >28 days: Resume at 1 lower dose
  • For recurrence: Permanently discontinue

• Grade 4

  • Permanently discontinue

Other adverse reactions

• Grade 2

  • Withhold until recovery to Grade ≤1
  • Resume at same dose

• Grade 3

  • Withhold until recovery to Grade ≤1
  • If recovery occurs in ≤28 days: Resume at same dose
  • If recovery occurs in >28 days: Resume at 1 lower dose

• Grade 4

  • Permanently discontinue

Strong and moderate CYP3A inhibitors

• Strong inhibitor: Avoid coadministration; if unavoidable, reduce dose to 320 mg BID x 4 days followed by 3 days off
• Moderate inhibitor: Reduce dose to 320 mg PO BID x 4 days followed by 3 days off
• After discontinuing strong or moderate CYP3A inhibitor, resume capivasertib dosage (after 3-5 half-lives of CYP3A inhibitor) that was taken before initiating strong or moderate CYP3A inhibitor

Renal impairment

• Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment required
• Severe (CrCl 15-29 mL/min): Not studied

Hepatic impairment

• Mild (bilirubin ULN or bilirubin >1-1.5x ULN and any AST): No dosage adjustment required
• Moderate (bilirubin >1.5-3x ULN and any AST): Monitor for adverse reactions due to potential increased capivasertib exposure
• Severe (bilirubin >3x ULN and any AST): Not studied